Examining antidepressant use in palliative care patients by risk of antidepressant discontinuation syndrome
Dr Maxine Glanger, Palliative Care Specialist, Specialist Palliative Care Service - NW Tasmania.
RANZCP Congress, Hobart, Tas, May 2021
The basic principle
• Antidepressants are hard to stop.
• Antidepressants are almost always oral medications.
• Dying patients stop swallowing and can't take their ADs.• This may go badly.
• You should think about it in the dying and medically unwell.
Relevance…
Psirides, Alex. The physiology of death and dying, 2016.
Antidepressants are commonly used in dying patients
Hotopf M, Chidgey J, Addington-Hall J, Lan Ly K. Depression in advanced disease: A systematic review part 1. Prevalence and case finding. Palliative Med. 2002;16(2):81-97.Irwin MR. Depression and insomnia in cancer: Prevalence, risk factors, and effects on cancer outcomes. Curr Psychiatry Rep. 2013;15(11).
Mood disorders:
• depression occurs in 15% of pts with advanced illness and up to 25% of cancer patients.
• anxiety occurs in nearly 20% of palliative care patients.
Symptom control:
• neuropathic pain• insomnia• nausea• pruritus• hot flushes• sialorrhoea• bladder overactivity
A little history…
1959Imipramine - the first effective antidepressant medication after a wide range of agents had been tried with unrewarding results
1960
Tranylcypromine (Parnate)
1961
Phenelzine (Nardil)
A little more history..
1961
Two years post-release there are reports of
“nausea, vomiting, dizziness, coryza, muscular pains and malaise”
at first regarded as conversion phenomena but subsequently attributed to physiological withdrawal.
TCA and MAOI withdrawal symptoms
Four groups of TCA withdrawal symptoms:• gastrointestinal and general somatic distress including
anxiety/agitation (cholinergic rebound)• sleep disturbance including vivid terrifying dreams• parkinsonism or akathisia• paradoxical mania
MAOI withdrawal is generally more severe and includes:• delirium• paranoia• hallucinations• severe rebound depression
Dilsaver SC, Greden JF, Snider RM. Antidepressant withdrawal syndromes: Phenomenology and pathophysiology. Int Clin Psychopharmacol. 1987;2(1):1-19Jenkins J, Glass S. Catastrophic complications related to psychopharmacologic drug withdrawal. Psychiatr Ann. 2016;46(8):466-72
Fast forward to 1988
The SSRIs
fluoxetine (1988)sertraline (1991)paroxetine (1992)fluvoxamine (1994) citalopram (1998)escitalopram (2002)
Reports of withdrawal phenomena from the early 1990s –after the introduction of sertraline, not fluoxetine
“AntiDepressant Discontinuation Syndrome” coined (ADDS)*
*Zajecka J, Tracy KA, Mitchell S. Discontinuation symptoms after treatment with serotonin reuptake inhibitors: A literature review. J CLIN PSYCHIATRY. 1997;58(7):291-7
Symptoms of SSRI withdrawal…
FINISH mnemonic*:• Flu-like symptoms (lethargy, fatigue, headache, achiness, sweating) • Insomnia (with vivid dreams or nightmares)• Nausea (sometimes vomiting)• Imbalance (dizziness, vertigo, light-headedness)• Sensory disturbances (“burning,” “tingling,” “electric-like” or “shock-like” sensations) • Hyperarousal (anxiety, irritability, agitation, aggression, mania, jerkiness)
*Berber MJ. FINISH: Remembering the discontinuation syndrome [2]. J CLIN PSYCHIATRY. 1998;59(5):255
SNRI withdrawal..
• Venlafaxine (1993), duloxetine (2004) and desvenlafaxine (2008) produce a very similar withdrawal syndrome
• Commonly headache, dizziness, nausea, light-headedness, excessive sweating, irritability, dysphoria, and insomnia*
• “Brain zaps” reported in patients withdrawing from either SSRIs or SNRIs
*Fava GA, Benasi G, Lucente M, Offidani E, Cosci F, Guidi J. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: Systematic review. Psychother Psychosom. 2018;87(4):195-203
Some atypicals - less likely to induce ADDS…
mirtazapine (1996)• useful in palliative care patients due to positive effects on nausea, insomnia and
dyspnoea• rare reports of withdrawal symptoms including withdrawal-emergent mania
moclobemide (2000)• one report of a flu-like withdrawal syndrome
agomelatine (2009)• does not induce an acute increase in synaptic serotonin• does not produce ADDS
vortioxetine (2013)• placebo-level withdrawal effects up to 2 weeks post-discontinuation
ADDS (antidepressant withdrawal)…
• is now listed in the DSM-5
• it is common with more than half of antidepressant users reporting symptoms - 46% of people experiencing symptoms report them as severe
• ADDS symptoms are not “brief and mild” - symptoms may be protracted and severe*
*Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence-based? Addict Behav. 2018
When is ADDS more likely?
Short half-life drugs:• drugs with a shorter elimination half-life are more likely to produce ADDS
symptoms, particularly paroxetine and venlafaxine• even brief interruption of paroxetine treatment can lead to ADDS symptoms• fluoxetine is the least likely SSRI/SNRI to produce ADDS – a double blinded trial of
fluoxetine continuation vs placebo substitution showed no difference in the groups up to 6 weeks
Longer duration of treatment
Rapid weaningHigher dose at cessation
Renoir T. Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: A review of the clinical evidence and the possible mechanisms involved. Front Pharmacol. 2013;4 APR Tint A, Haddad PM, Anderson IM. The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: A randomised study. J Psychopharmacol. 2008;22(3):330-2 Zajecka J, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaum J, et al. Safety of abrupt discontinuation of fluoxetine: A randomized, placebo- controlled study. J Clin Psychopharmacol. 1998;18(3):193-7
Mechanisms have not been fully elucidated but may include:• a rapid drop in synaptic serotonin particularly with short half-life agents• cholinergic rebound (TCAs)• secondary effects on other receptor systems including:
Noradrenaline (MAOIs)GABADopamine
Possible mechanisms
Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, et al. Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. J CLIN PSYCHIATRY. 1997;58(SUPPL. 7):23-7
The study
Retrospective chart review of 222 patients who died under the care of a palliative care service in a 12-month period.
Written and electronic palliative care service and hospital records examined.
Inclusion:
• 18+ years old at admission to the service• cared for by the service for more than 1 month
• 472 deaths in 12 months minus 1pt <18yrs minus 249 cared for for < 1 month = 222
Location:
• Specialist Palliative Care Service - Northwest Tasmania
• services 100 000 people across rural and remote communities• regional and community hospitals, residential aged care and homes
• there was no hospice facility
Our study looked at antidepressant use and potential risk NOT prevalence of ADDS symptoms, however several interesting cases of ADDS were noted
Median age at death 74.5yrs
Male 57.7% Female 42.3%
171 (77%) had malignant diagnoses 51 (23% had non-malignant diagnoses)
5 most frequent diagnoses:• lung cancer (18%)• colorectal cancer (9%)• pancreatic cancer (8%)• breast cancer (5%)• chronic obstructive pulmonary disease (5%)
Demographics and diagnoses….
The ugly the bad
and the good
Antidepressants classifiedby risk of ADDS
We examined antidepressant use…
At referralDuring the course of
care
In the last month of life
Results
Nearly 40% of patients were on an antidepressant at some point during care
At referral During care Last month of life
62/222 (30%) on ADs 31/222 (14%) started on or switched to new AD
61/222 (27%) on ADs
- 9 on high-risk AD- 36 on mod-risk AD- 17 on low-risk AD
- 1 on high-risk AD- 21 on mod-risk AD- 9 on low-risk AD
- 6 on high-risk AD- 35 on mod-risk AD- 20 on low-risk AD
73% on moderate to high-risk AD
71% started on moderate to high-risk AD
67% of patients still on ADs on moderate to high-risk AD
Most common ADs:Mirtazapine Amitriptyline Paroxetine Citalopram Escitalopram
Most common ADs:Amitryptyline Mirtazapine Duloxetine
Most common ADs:MirtazapineAmitriptylineEscitalopramCitalopramVenlafaxine
Real stories from our chart review…
A 48-year-old man with advanced lung cancer developed dysphagia a week before death resulting in abrupt cessation of venlafaxine 225mg.
He became severely agitated and required frequent high doses of midazolam and haloperidol in the days before death.
Real stories from our chart review…
A 66-year-old male with head and neck cancer ceased daily paroxetine 20mg with onset of dysphagia. Four days later he became highly anxious and delirious.
Sublingual mirtazapine was commenced with gradual improvement of his symptoms.
Oral intake may be interrupted or become impossible in people with terminal illness..
Interrupted swallowing Nausea/vomiting/poor absorption Medication error
Xerostomia and oral infectionsMucositis • Chemotherapy• RadiotherapyTumour invasion or compressionNeuromuscular • brain tumour• MND• Parkinson’s disease• stroke
Malignant bowel obstruction.Chemo/radiotherapy induced nausea/vomiting.Metabolic disturbance• Hypercalcaemia• Uraemia• Liver failureOpiatesConstipation
Cognitive issues• Delirium• Fatigue• Medication induced sedationPrescribing or charting errors• Multiple hospital admissions• Multiple prescribersOverenthusiastic deprescribing(palliative care doctors plead guilty!)
When tablets become problematic…
Bogaardt Hder Heide A, van Zuylen L, Speyer R. Swallowing Problems at the End of the Palliative Phase: Incidence and Severity in 164 Unsedated Patients. Dysphagia. 2015;30(2):145-51 , Veerbeek L, Kelly K, van
70% of unsedated (i.e. AWAKE) patients stop being able to swallow tablets in the days before death.
Mitigating ADDS in palliative care patients
Think about it!
Consider:• using a low-risk antidepressant if starting one• tapering antidepressants slowly if not needed or switching to fluoxetine• continuing a higher-risk antidepressant at the lowest effective dose• using antidepressants which are available in alternate forms (next slide)• covering symptoms during periods of interrupted oral intake or EOL with clonazepam*
Please consider drug interactions if swapping antidepressants (e.g. tamoxifen and fluoxetine)
Mitigating ADDS in palliative care patients
*Fava GA, Belaise C. Discontinuing antidepressant drugs: Lesson from a failed trial and extensive clinical experience. Psychother Psychosom. 2018;87(5):257-67
Commercially available alternative formulations:• mirtazapine oral disintegrating tablet, fluoxetine dispersible tablet, escitalopram liquid
Crushable tablets:• citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, amitriptyline,
imipramine, nortriptyline, mirtazapine (regular tablets), moclobemide, vortioxetineDispersible:
• citalopram, escitalopram, fluoxetine, sertraline, nortriptyline, duloxetine Openable:
• Effexor brand of venlafaxine onlyUnmodifiable:
• desvenlafaxine – don’t even try - “Don’t mess with Des”
Love your pharmacist
*Society of Hospital Pharmacists of Australia. Don’t Rush to Crush. 3rd ed. 2018
Antidepressant formulations*
Thank you for listening..“Examining antidepressant use in palliative care patients by risk of antidepressant discontinuation syndrome” is accepted for publication in Internal Medicine Journal.
LimitationsWe did not have access to:
GP records, RACF notes, community pharmacy data, PBS data
Single-centre study may limit wider applicability
We based our risk-ranking on a thorough reading of all available literature including systematic reviews of individual drug classes but did not undertake a comparative systematic review across all classes.
Contact: [email protected]
Thanks toProf Greg Peterson – research supervisor extraordinaire
Prof Gin Malhi – for not thinking the concept was completely mad
Arun Abraham – trusty offsider
Yelena Fridgant – RedCap warrior
Emma Hooper – pharmacy Diva
Dr Rosemary Ramsay, Helen Morse and the staff of the SPCS -Northwest Tasmania
Tasmanian Health Service – NW – for use of data
The doctors and nurses of the SPCS – Southern Tasmania